The advent of comprehensive genomic resources has led to the rapid identification of novel genes with potential roles in regulating cellular proliferation, but only limited approaches to define their role within functional pathways and their contribution to human cancer. Genome projects in multiple organisms have underscored the evolutionary conservation of cellular proliferation pathways between man and simpler organisms, and it is the goal of this P01 application to provide a bridge between studies in genetic model organisms and human cancer. The use of screens for novel genes involved in cell proliferation and cell cycle regulation based in Drosophila and C. elegans will lead to the discovery of mammalian orthologs, whose role in human cancer will be assessed by mutational studies. C. elegans and Drosophila also provide efficient tools, such as RNA interference (RNAi), for the functional analysis of novel genes identified in these screens and in mammalian genomic screens targeting homozygous deletions in mouse tumor models. Project 1 (Dyson): Identify novel modifiers of the cell cycle regulators E2F and retinoblastoma (RB) in Drosophila, isolate their mammalian orthologs, and search for mutations in human cancers. Project 2 (Hariharan): Use a recombination-driven screen in the Drosophila eye for genes whose homozygous inactivation triggers increased cellular proliferation, characterize promising candidates, including a novel gene Salvador, and determine whether it is targeted by mutations in human tumors. Project 3 (Haber): Adapt Representational Difference Analysis (RDA) to screen for homozygous genomic deletions in a mouse tumor model of cancer progression, characterize DOS, a novel gene implicated in Rho signaling that is targeted by such a deletion, use RNAi to analyze novel genes present within tumor-associated deletions. Project 4 (van den Heuvel): Use C. elegans to search for genes that modulate the function of D-type cyclins, characterize two novel negative regulators, lin-9 and lin-36, and define their contribution to human cancer. These projects will be supported by cores for Administration (Haber), Genetics (Drosophila: Artavanis-Tsakonas, and C. elegans: Hart), and Molecular Pathology (expression: Stamenkovic, and mutational analysis: Bell). Collectively, these studies provide a concerted effort to make use of powerful tools provided by genetic model systems to define the function of new genes involved in cellular proliferation and their potential roles in human cancer.